The long-term goals of this Program Project in the Pathophysiology of Human Growth are to understand the cellular, molecular, genetic, and developmental factors involved in the control of normal human growth, and to use this information to develop new strategies for the diagnosis and treatment of human growth disorders. It is anticipated that the knowledge gained from the studies planned during the upcoming project period will give insight into the regulation of growth factor gene expression, will enhance understanding of the mechanisms of growth factor biosynthesis, protein processing, and delivery to sites of action, will provide information about the specificity and mechanisms of growth factor signal transduction pathways, and will lead to new insights into the molecular physiology of growth factor action. Toward these aims, the specific objectives of this research program include the following: Project I: To define and characterize the signaling pathways that regulate human insulin-like growth factor (IGF-I) gene transcription. (Dr. P. Rotwen) Project II: To understand the mechanisms that control the bioavailability of human IGF-I, in particular to define the steps regulating proteolytic processing of the IGF-I precursors, and to identify the post-translational mechanisms influencing the bio-activity of IGF binding proteins. (Dr. S. E. Tollefsen) Project III: To understand a key step in growth factor-mediated signal transduction by analyzing the structure, function, and regulation of phosphatidylinositol 4-P phosphatase, a critical enzyme in phosphatidylinositol metabolism. (DR. L.J.Pike) Project IV: To define the roles of the IGF system in regulating trophoblast growth, differentiation, and metabolism. (Drs. M. Fant and C. Smith)